PROJECT SUMMARY/ABSTRACT Dramatic increases in longevity observed in the past century have come with an added price: increased prevalence of age-related cognitive disorders, such as Alzheimer's' disease (AD), that impose significant burden on individual and societal resources. There is no cure for AD or other dementias, and shifting the investigation beyond the framework of ?-amyloid accumulation and focus on identifying the harbingers of disease at the earliest possible time is critical. As AD is diagnosed clinically by examining primarily declines in episodic memory, investigation of neural functions that are associated with that cognitive domain and that may change before behavioral deficits are apparent, is a highly plausible choice for discovery of a prospective early biomarker of disease. A key candidate is glutamate (Glu) because of its ubiquity in the cerebral neurotransmission mechanisms and its fundamental role in mnemonic processes leading to a highly plausible target in this search. Although the notion of glutamatergic dysfunction associated with memory declines in AD and normal aging has garnered empirical support, no direct in vivo evidence of changes in memory-related Glu modulation among older adults is available. Examining age difference and age-related changes in task-related Glu modulation is the main aim of this study. To advance this goal, we introduce, with compelling preliminary data, the application of in vivo H fMRS, a highly novel method for quantifying in real-time the task-related modulation of Glu. We will assess Glu modulation within the hippocampus (HC), while older and younger participants engage in an associative learning and memory task that we have established as a robust, specific hippocampal challenge in preciously published work. H fMRS provides real-time task-related changes in Glu that is independent of vascular confounds as is with BOLD fMRI and at a temporal resolution of under a minute. The task, the brain location, and the choice of the neurotransmitter (Glu) are highly relevant to aging and AD. We will acquire a structural MRI of the whole brain, a high-resolution scan of the hippocampal body that allows measurement of the HC subfields, and a 1H fMRS of the HC during encoding and retrieval of object-location associations in 36 healthy young (21-30-year-old) and 36 healthy older (60-70-year-old) participants. The procedure will be repeated after one year. This high-risk high-yield study aims to establish Glu modulation changes as a viable early marker of cognitive decline in the context of structural HC changes and decline in memory performance. The knowledge advancement from this study will be demonstration of a link between changes in task-related Glu modulation in the older adults, HC volume and memory over time. This study will provide important foundations for future multi-occasion longitudinal studies that will advance understanding of individual differences in cognitive development in the late part of the lifespan without misleading inferences from cross-sectional studies and provide a foundation for intervention aimed at mitigating cognitive declines.